Pharmacotherapy for Liver Cirrhosis and Its Complications 981192614X, 9789811926143

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Pharmacotherapy for Liver Cirrhosis and Its Complications Xingshun Qi Yongping Yang Editors

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Pharmacotherapy for Liver Cirrhosis and Its Complications

Xingshun Qi  •  Yongping Yang Editors

Pharmacotherapy for Liver Cirrhosis and Its Complications

Editors Xingshun Qi Department of Gastroenterology General Hospital of Northern Theater Command Shenyang, China

Yongping Yang Faculty of Liver Disease of Chinese People’s Liberation Army General Hospital The Fifth Medical Center of the Chinese People’s Liberation Army General Hospital Beijing, China

ISBN 978-981-19-2614-3    ISBN 978-981-19-2615-0 (eBook) https://doi.org/10.1007/978-981-19-2615-0 © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2022 This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Singapore Pte Ltd. The registered company address is: 152 Beach Road, #21-01/04 Gateway East, Singapore 189721, Singapore

Foreword

Hepatology is a constantly active and dynamic field, in which a lot of progress has been seen in the last two decades in different areas, such as epidemiology, development of new tools for the diagnosis and assessment of chronic liver disease progression, treatment, and complications. At the present time, it is known that the worldwide morbidity and mortality rates for chronic liver disease and cirrhosis are increasing. The main causes of chronic liver disease are alcohol, viral hepatitis B and C, metabolic dysfunction-associated fatty liver disease (MAFLD), and autoimmune and cholestatic liver disease. In spite of the fact that MAFLD has been considered mainly a problem in Western countries, several studies have reported a growing prevalence of MAFLD in Asia. The increasing prevalence of MAFLD in Asian countries is associated with the growing trend of obesity in this geographical area, which is why it has been reported that the current prevalence of MAFLD in Asia approaches the worldwide MAFLD prevalence of 25% to 30%. Thus, hepatitis B virus and MAFLD are currently the main causes of liver cirrhosis in eastern countries. Regarding the pathophysiology of liver cirrhosis, initial fibrosis results from chronic damage to the liver in conjunction with the accumulation of extracellular matrix proteins, which is a characteristic of most types of chronic liver diseases. These alterations in turn distort the hepatic architecture by forming a fibrous scar, with the subsequent development of nodules of regenerating hepatocytes v

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Foreword

defining cirrhosis. Patients with cirrhosis who experience hepatic decompensation, such as with the development of portal hypertension, ascites, hepatic encephalopathy, portal vein thrombosis, hepatorenal syndrome, and spontaneous bacterial peritonitis are at higher mortality risk. Management should be focused on the prevention of the recurrence of complications, some of which now can be treated specifically. The Pharmacotherapy for Liver Cirrhosis and Its Complications, edited by Dr. Xingshun Qi, a very recognized young hepatologist, includes 14 chapters written by an international group of experts from seven countries such as China, United States, Argentina, India, Thailand, Austria, and Canada. This book aims to bring to the readers' attention the latest advances in pharmacotherapy for liver cirrhosis and its complications. The book offers a variety of topics in the field of hepatology such as the use of antiviral drugs for HBV and HCV, anticoagulants, antibiotics, ursodeoxycholic acid, the use of human serum albumin infusion, non-selective beta-blockers, somatostatin and octreotide, terlipressin, diuretics, statins, L-Ornithine L-Aspartate, and lactulose. Each chapter is structured in a clear and comprehensive fashion, in conjunction with the description of practical applications. Undoubtedly, the editor and authors must be congratulated for their far-reaching efforts. Faculty of Medicine National Autonomous University of Mexico Mexico City, Mexico

Nahum Méndez-Sánchez

Preface

Liver cirrhosis, end stage of chronic liver diseases, is one of the leading causes of death worldwide, primarily due to its secondary severe complications, including ascites, acute variceal bleeding, portal vein thrombosis, hepatic encephalopathy, and liver and renal failure. Currently, liver transplantation remains the sole curative treatment option for liver cirrhosis. Besides, the efficacy and safety of “new” drugs for the prevention and treatment of liver cirrhosis related complications have been widely explored, and meanwhile, the indications of “old” drugs are further confirmed and even expanded. Undoubtedly, such advances are potentially effective for the improvement of patients’ outcomes. For this reason, Prof. Yongping Yang and I decided to launch this book project to summarize the current status regarding pharmacotherapy for liver cirrhosis and its complications. Finally, a panel of famous experts, who are very skilled at the management of liver cirrhosis and have published high-impact papers related to this topic, have been invited to write a total of 14 chapters regarding etiological treatment of hepatitis B and C infection and cholestasis related liver cirrhosis, prevention and treatment of major liver cirrhosis related complications, and some promising drugs for the improvement of survival of patients with liver cirrhosis. Shenyang, China March 18, 2022

Xingshun Qi

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Acknowledgement

In the contemporary era, emerging medical knowledge can be rapidly disseminated, which is very helpful for physicians to effectively prevent and treat various diseases and for patients to understand them. Such a great benefit is contributed to a certain extent by the development of publishers. Therefore, I should appreciate this valuable opportunity provided by the Springer Nature publisher for launching and finalizing this current book project. Notably, Miss Joyce Zhou, who is an in-house editor of the Springer, and Mr. Kumar Athiappan, who is a coordinator of the book project, have given me lots of guidance and assistance in the book preparation. A book cannot be finished without great efforts of authors. It should be acknowledged that all chapter authors have made their contributions to this book project. Notably, some authors have revised their chapters for many times to achieve the publication level, despite their heavy engagement in clinical practice and academic research. Finally, as I have acknowledged in my first three Springer Nature books, I must be thankful for the life-long support of my wife, Jun Liu, and my family. Xingshun Qi

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Contents

1

 Anti-HBV Drugs in Liver Cirrhosis ��������������������������������������������������������   1 Qing-Lei Zeng

2

 Antiviral Therapy for Hepatitis C Virus Infection in Cirrhosis������������  11 Yunyu Zhao, Xinyuan He, and Fanpu Ji

3

 Anticoagulants and Antiplatelet Agents in Cirrhosis ����������������������������  23 Feng Su and Patrick G. Northup

4

 Antibiotics in Liver Cirrhosis ������������������������������������������������������������������  49 Swati Chouhan, Prajna Anirvan, and Shivaram Prasad Singh

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 Ursodeoxycholic Acid in Liver Cirrhosis: An Evidence-Based Review ��������������������������������������������������������������������������������������������������������  69 Kanokwan Pinyopornpanish

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 Ursodeoxycholic Acid in Liver Cirrhosis: A Chinese Perspective ��������  81 Wenkang Gao, Zhonglin Li, Huikuan Chu, Hang Yuan, Lilin Hu, Lin Yao, Li Zhang, Weijun Wang, Rong Lin, and Ling Yang

7

 Human Serum Albumin Infusion in Liver Cirrhosis������������������������������ 113 Zhaohui Bai, Meijuan Zou, Xiaoying Zhang, and Gang Cheng

8

 Non-selective Beta Blockers in Liver Cirrhosis�������������������������������������� 127 Mathias Jachs and Thomas Reiberger

9

 Somatostatin and Octreotide in Liver Cirrhosis������������������������������������ 141 Arpan Mohanty

10 Terlipressin  in Liver Cirrhosis������������������������������������������������������������������ 149 Florence Wong and Tilman Sauerbruch 11 Diuretics  in Cirrhotic Patients with Ascites�������������������������������������������� 167 Ran Wang, Lu Chai, and Xiaozhong Guo 12 Statins  in Liver Cirrhosis�������������������������������������������������������������������������� 179 Alberto E. Muñoz, Mariano Cartier, and Ayelén B. Kisch

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Contents

13 L-Ornithine  L-Aspartate for the Prevention and Treatment of Liver Cirrhosis and its Complications������������������������������������������������ 205 Roger F. Butterworth 14 Lactulose  in Liver Cirrhosis��������������������������������������������������������������������� 223 Jessica Faccioli, Stefania Gioia, Silvia Nardelli, Oliviero Riggio, and Lorenzo Ridola

1

Anti-HBV Drugs in Liver Cirrhosis Qing-Lei Zeng

Abstract

Cirrhosis is one of the severe consequences of chronic hepatitis B, and it is more likely to progress to decompensated form and hepatocellular carcinoma without antiviral treatment. Currently, the preferred first-line antiviral agents for compensated cirrhosis include peginterferon α, entecavir, tenofovir disoproxil fumarate, and tenofovir alafenamide. Notably, in patients with decompensated cirrhosis, peginterferon α is contraindicated due to its safety concerns, and tenofovir alafenamide is not officially recommended due to limited administration data. The oral antiviral treatment duration for compensated cirrhosis is indefinitely long-­ term, and lifelong antiviral treatment is recommended for all patients with decompensated cirrhosis. Recent studies have demonstrated that high rates of compensated cirrhosis can be regressed, and high rates of decompensated cirrhosis can be recompensated after long-term antiviral therapy, accompanying with the decreasing risk of liver transplantation and hepatocellular carcinoma. Keywords

Compensated cirrhosis · Decompensated cirrhosis · Antiviral treatment Peginterferon α · Entecavir · Tenofovir disoproxil fumarate · Tenofovir alafenamide

Q.-L. Zeng (*) Department of Infectious Diseases and Hepatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2022 X. Qi, Y. Yang (eds.), Pharmacotherapy for Liver Cirrhosis and Its Complications, https://doi.org/10.1007/978-981-19-2615-0_1

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Q.-L. Zeng

Table 1.1  Approved antiviral agents in adults with HBV-related cirrhosis Drug Peg-­ IFN αa ETV TDF TAF

Dose in adults α-2a 180 μg, α-2b 100 μg, weekly 0.5 mg dailyb 300 mg daily 25 mg daily

C-cirrhosis Yesb

D-cirrhosis No

Yes

Yes

Yes

Yes

Yes

Yesc

Treatment duration 48 weeks

Indefinite or lifelong Indefinite or lifelong Indefinite or lifelong

Potential side effects Flu-like symptoms, fatigue, mood disturbances, cytopenia, autoimmune disorders, anorexia, weight loss Lactic acidosis (D-cirrhosis only) Nephropathy, Fanconi syndrome, osteomalacia Lactic acidosis

a  Peg-IFN α can be used in patients with well-compensated cirrhosis. bEntecavir of 1.0 mg daily for decompensated cirrhosis. cNot officially approved but it is reasonable to be used. C-cirrhosis compensated cirrhosis; D-cirrhosis decompensated cirrhosis

Hepatitis B virus (HBV)-related cirrhosis is the severe stage of chronic hepatitis B (CHB) and has higher risk of developing hepatocellular carcinoma (HCC) than non-­ cirrhotic patients, although HBV can cause HCC even in patients who do not have cirrhosis. In general, cirrhosis can be divided into two forms, i.e., compensated and decompensated cirrhosis, and the latter is commonly characterized by the presence of one or more complications of ascites, bleeding from the esophageal and gastric varices, and hepatic encephalopathy. Antiviral treatment should be initiated in all patients with compensated cirrhosis with detectable HBV DNA and any alanine aminotransferase (ALT) level. Meanwhile, all hepatitis B surface antigen (HBsAg) positive patients with decompensated cirrhosis should be treated with nucleos(t)ide analogs (NA) with high barrier to resistance, irrespective of HBV DNA and ALT levels. Additionally, patients with decompensated cirrhosis should be treated in specialized liver units or inpatient departments to achieve the clinical recompensation. Encouragingly, more and more clinical studies demonstrated that HBV-related cirrhosis can be reversed or alleviated by long-term anti-HBV therapy, especially the Lancet “Regression of Cirrhosis Study” published online at the end of 2012 by Marcellin et al. [1]. Given that the current first-line antiviral agents are peginterferon α (Peg-IFN α), entecavir (ETV), tenofovir disoproxil fumarate (TDF), and tenofovir alafenamide (TAF) (Table 1.1) [2–4], this chapter mainly focuses on the role of these drugs for the treatment of HBV-related cirrhosis.

1.1

Anti-HBV Drugs in Compensated Cirrhosis

1.1.1 Pegylated-Interferon α Peg-IFN α in regimens similar to those administered in CHB can be considered for the treatment of compensated cirrhosis, especially for patients who require

1  Anti-HBV Drugs in Liver Cirrhosis

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short-­ term treatment and high probability of sustained off-therapy response, although adverse events like thrombocytopenia are more obvious and need more careful management. The standard treatment duration is 48 weeks, and the extension of the duration of peg-IFN α therapy beyond 48 weeks may be beneficial in selected patients, therefore, response-guided therapy can be considered for cirrhotic patients. Notably, the potential benefit from peg-IFN α treatment on the HCC incidence seems to be superior to that of NA therapy, especially in Asian patients [5], although HCC may still develop after sustained off-treatment responses based on peg-IFN α treatment, particularly in cirrhotic patients [3]. In a previous study, 70 advanced fibrotic (Ishak fibrosis score 4–6) CHB patients underwent peg-IFN α-2b; meanwhile, 169 patients without advanced fibrosis who received peg-IFN α-2b plus lamivudine combination therapy were the control group, with the treatment duration of 48  weeks; and the virologic response was defined as hepatitis e antigen (HBeAg) seroconversion plus HBV DNA